PORPHYRIN PI-CATION AND PROTEIN RADICALS IN PEROXIDASE CATALYSIS AND INHIBITION BY ANTITHYROID CHEMICALS

1. Thyroid peroxidase (TPO) catalyses the iodination and phenolic coup ling reactions in the biosynthesis of thyroid hormones. 2. The two-ele ctron oxidation of TPO by H2O2 produces an oxoferryl porphyrin pi-cati on radical compound I that isomerizes spontaneously to a form of compo und I that contains an oxoferryl haem and the second oxidizing equival ent as an amino acid radical. 3. The pi-cation radical compound I is t he catalytic species that effects iodide ion oxidation and the protein radical compound I is most likely the catalytic species that catalyse s coupling. 4. Methimazole, a therapeutic, anti-hyperthyroid drug, is a suicide substrate for TPO and effects irreversible inactivation by T PO-mediated S-oxygenation to a reactive sulphenic acid that binds cova lently to the prosthetic haem. 5. Sulphamethazine and other arylamines containing electron-withdrawing substituents inhibit TPO compound I-m ediated reactions by reversible, mixed-type inhibition. 6. Ethylenethi ourea, a fungicide metabolite, blocks TPO-mediated iodination by react ing with the catalytic iodinating species as an alternate substrate. 7 . Resorcinol and related dietary flavonoids are suicide substrates for TPO and act by covalent binding to amino acid residues, presumably th ose radical sites present in the compound I isomer. 8. Nitrosobenzene, a known radical-trapping agent, blocks TPO-mediated coupling but not iodination or phenolic oxidations presumably by interception of the 3, 5-diiodotyrosyl radical species generated during the coupling reaction .